Monica Vegiraju

Introduction. During pregnancy, maternal use of nicotine exposes the fetus to many teratogenic chemicals. These markedly affect the fetal brain and lung development, causing permanent damage.¹ Nicotine, a potent vasoconstrictor, results in less oxygen and nutrient delivery to the fetus, causing low fetal birth weight.² There is also a higher risk of sudden infant death syndrome and birth defects, like cleft palate.¹ CDC scientists also found that among the 10% of pregnant women that reported current alcohol use, 40% of these women also reported use of another substance, mostly nicotine.³ Because this is still an emerging area of research, the current hypothesis in how nicotine causes its damage in the fetus is through endoplasmic reticular stress involving the unfolded protein response pathway.⁴ Methods. Female rats received daily subcutaneous injections of saline or nicotine bitartrate. Western blot and RT-PCR were used to analyze phosphorylated PERK, CHOP, PDI, QSOX1, VKORC1, Hif1α, and GCN2.⁴ In another study, virgin female mice were exposed to 2 cigarettes 2x daily for 6 weeks prior to mating and during gestation and lactation. RT-PCR was used to asses gene expression and western blot to measure protein levels of EGR-1, Hif1α, MnSOD, and translocase of outer membrane TOM20 and OXPHOS proteins.⁵ Results. The ratio of phosphorylated ERK to unphosphorylated ERK was significantly elevated in the nicotine exposed group. CHOP mRNA and protein levels were also significantly elevated in this group, but its downstream effectors, Bax and Bcl-2, did not show significant increases with nicotine exposure. This could be due to the time point at which tissues were obtained for protein and mRNA analyses. It  is feasible that the effects of CHOP on downstream effectors were delayed in time. PDI, protein disulfide isomerase, and QSOX1, an ER oxidoreductase, both had decreased protein levels in nicotine exposed placentas, implying impaired disulfide bond formation. Disulfide bond formation is intimately connected with ER homeostasis and has been known to cause ER stress when compromised.⁴ There were also significantly elevated levels of IL1R, IL6, and TLR4, indicating the presence of inflammation that has also been implicated in the UPR pathway and ER stress.⁵ Conclusions. Activation of PERK in the UPR pathway indicates that ER stress is occurring. The presence of upregulation of UPR pathway markers along with apoptotic markers suggests that many of nicotine’s harmful effects on the fetus are related to increased ER stress, inflammation, and impaired disulfide bond formation.

1. Tobacco, Alcohol, Drugs, and Pregnancy. ACOG. https://www.acog.org/womens-health/faqs/tobacco-alcohol-drugs-and-pregnancy. Accessed May 16, 2021.
2. Günther V, Alkatout I, Vollmer C, Maass N, Strauss A, Voigt M. Impact of nicotine and maternal BMI on fetal birth weight. BMC Pregnancy Childbirth. 2021;21(1):127. Published 2021 Feb 12. doi:10.1186/s12884-021-03593-z
3. Polysubstance Use in Pregnancy. Centers for Disease Control and Prevention. https://www.cdc.gov/pregnancy/polysubstance-use-in-pregnancy.html. Published November 25, 2020.
4. Wong MK, Nicholson CJ, Holloway AC, Hardy DB (2015) Maternal Nicotine Exposure Leads to Impaired Disulfide Bond Formation and Augmented Endoplasmic Reticulum Stress in the Rat Placenta. PLoS ONE 10(3): e0122295. doi:10.1371/ journal.pone.0122295
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